NM_006790.3:c.372delA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_006790.3(MYOT):​c.372delA​(p.Ala125LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MYOT
NM_006790.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.304
Variant links:
Genes affected
MYOT (HGNC:12399): (myotilin) This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]
PKD2L2-DT (HGNC:55557): (PKD2L2 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYOTNM_006790.3 linkc.372delA p.Ala125LeufsTer5 frameshift_variant Exon 3 of 10 ENST00000239926.9 NP_006781.1 Q9UBF9A0A0C4DFM5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYOTENST00000239926.9 linkc.372delA p.Ala125LeufsTer5 frameshift_variant Exon 3 of 10 1 NM_006790.3 ENSP00000239926.4 A0A0C4DFM5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251408
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461804
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Oct 10, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported previously in two patients from a cohort of patients with unexplained limb-girdle muscle weakness; however, no specific clinical information was provided (PMID: 32528171); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 32528171) -

Myofibrillar myopathy 3 Uncertain:2
Sep 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with clinical features of MYOT-related conditions (PMID: 32528171). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 464370). This variant is present in population databases (rs781353247, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ala125Leufs*5) in the MYOT gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYOT cause disease. -

Oct 26, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781353247; hg19: chr5-137211532; API